Keteneylidenetriphenylphosphorane as a 'C2O building block' in the synthesis of highly functionalised tetramic and tetronic acids

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Keteneylidenetriphenylphosphorane as a 'C

₂

O building block' in the synthesis of highly functionalised tetramic and tetronic

acids.

Vorgelegt von Claire Melanophy, BSc

Dissertation

zur Erlangung des Doktorgrades

der Fakultät für Biologie, Chemie und Geowissenschaften Universität Bayreuth und

School of Chemistry, Queens University, Belfast.

Bayreuth, 2004

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Acknowledgements

Firstly, I would like to thank my supervisor Prof. Dr. R. Schobert for his help and support throughout my PHD.

Many thanks to my colleagues: Dr Gary, Gillian, Ralf, Sponge Thomas, Andreas, Sven and Herman, with whom I had many laughs in the lab and especially to Juan who took time out to help me with computer stuff and Carsten for his translation expertise.

I would like to thank the staff of OCI: Werner, Rosie, Kerstin (NMR) and Michael (MS) for their friendliness and help, and Claus who was especially supportive of me. I would also like to acknowledge the kindness of the Unverzagt group when I came to Bayreuth, especially Markus and Stefano, I really appreciate it. I must also extend my heartfelt gratitude to the staff of the Chemistry department in Queens University: QUBIS (CHN services), Robert and Manus (Mass spectral services) and Richard and Conor (NMR spectral services) who were always there for a wee chat.

A special thanks to Dr Peter Goodrich and Dr Alistair King, who were always there to help me out with chemistry and from whom I learned a lot! Thank you both for proof- reading my thesis.

I would like to say a BIG THANK YOU to my luvely fella, Flo, for his support throughout my writing-up, the proof-reading and advice, and the wee trips away which were badly needed.

And last but by no means least, heartfelt thanks to each of my family members, Paul, Brenda and Colleen, who have always been there for me. I would especially like to thank my mum and dad for their endless support, both emotionally and financially, throughout the course of my university education. Thank You ♥.

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I dedicate this thesis to my Mum and Dad without whom none of this would have been possible.

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This research was carried out from October 1999 to September 2001 in the School of Chemistry, Queens University of Belfast, and from October 2001 to May 2003 in the Department of Organic Chemistry I, University of Bayreuth, under the supervision of Prof. Dr. Rainer Schobert.

Vollständiger Abdruck der von der Fakultät Biologie, Chemie und Geowissenschaften der Universität Bayreuth zur Erlangung des akademischen Grades eines Doktors der Naturwissenschaften genehmigten Dissertation.

Promotionsgesuch eingereicht am : 28. April 2004 Tag der mündlichen Prüfung : 22. Juli 2004

Erstgutachter : Prof. Dr. Rainer Schobert Zweitgutachter : Prof. Dr. Carlo Unverzagt

Prüfungsausschuss : Prof. Dr. G. Krauss Prof. Dr. K. Dettner

Prof. Dr. K. Seifert (Vorsitz)

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Abstract

Naturally occurring 4-hydroxy-pyrrol-2(5H)-ones and 4-hydroxy-furan-2(5H)-ones are known to possess a wide range of biological activities such as anti-viral and tumour inhibition. For this reason, the synthesis of a number of these compounds was attempted, namely Tenuazonic Acid, Reutericyclin and Carlosic acid.

A general synthesis of 4-hydroxy-pyrrol-2-ones was established by reaction of a phosphorus ylide (Ph3PCCO) with a variety of amino esters. A number of derivatives were prepared with varying substituents at the 3- and 5-positions of the nitrogen heterocycle. A general method for the preparation of highly functionalised furan-2-ones from simple α-hydroxy esters was also developed.

Progress has been made in the synthesis of N-substituted pyrrol-2-ones where simple amide esters were reacted with a phosphorus ylide (Ph3PCCO) in the construction of highly functionalised nitrogen heterocycles.

A new acylation procedure was developed in order to selectively introduce an acetyl residue to pyrrolidine-2-ones and furan-2-ones. A phosphorus ylide (Ph3PCCO) and its solid supported variant were used as acylating agents under relatively mild, basic conditions.

Complex heterocycles were prepared using the Diels-Alder methodology and from reaction of Ph3PCCO with relatively simple molecules.

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Abstrakt

Natürlich vorkommende 4-Hydroxy-pyrrol-2(5H)-one und 4-Hydroxy-furan-2(5H)-one besitzen hohe biologische Aktivität. So zeigen sie unter Anderem anti-virale als auch anti-tumour Eigenschaften. Auf Grund dessen wurde versucht einen synthetischen Zugang zu Tenuazonsäure, Reutericyclin und Carlosischer Säure, zu finden.

Ein allgemeiner Syntheseweg zur Herstellung von 4-Hydroxy-pyrrol-2-onen wurde durch die Reaktion von Phosphor Ylid Ph3PCCO mit verschiedenen Aminosäureestern etabliert. Durch die Einführung von verschiedenen Substituenten der 3- und 5-Positionen des Stickstoff-Heterocyclus wurde eine Vielzahl von Derivaten synthetisiert. Zusätzlich wurde auch eine allgemeine Syntheseroute zur Herstelllung von hochfunktionalisierten Furan-2-onen ausgehend von α-Hydroxyestern.

Deutliche Fortschritte in Bezug auf die Synthese von N-substituierten Pyrrol-2- onen wurden verzeichnet. Durch Umsatz von einfachen α-Amidoestern mit Phosphor Ylid Ph3PCCO wurden hochfunktionalisierten wurden Stickstoff-Heterocyclen erhalten.

Ein neuen Acylierungsmethode zur selektiven Einführung von einem Acetylrest in Pyrrol-2-one und Furan-2-one konnte gefunden und etabliert werden. Phosphor Ylid (Ph3PCCO) und dessen festphasengebundene Variante wurden als Acylierungmittel verwendet. Diese Reaktion wurde unter milden und basischen Bedingungen durchgeführt.

Komplexe Heterocycle wurden mittels der Diels-Alder Methode als auch der Reaktion von Ph3PCCO mit relativ einfachen Molekülen hergestellt.

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Objectives

The aim of this project was to synthesise a number of biologically active 3-acyl-4- hydroxy-5-alkyl-pyrrol-2-ones and 3-acyl-4-hydroxy-5-functionalised-furan-2-ones using a phosphorus ylide (Ph3PCCO) as a C2O (carbon-oxygen) source to construct the heterocyclic nucleus. Using this approach, the objectives of this project were:

• Development of a general procedure for the preparation of 5-alkyl-pyrrolidine- 2,4-diones, starting from amino acids.

• Investigation of common acylation procedures to selectively introduce a 3-acyl substituent to the sensitive pyrrolidine-2,4-dione nucleus.

• Reaction of amide esters with Ph3PCCO to generate highly functionalised nitrogen heterocycles.

• Preparation of complex furan-2-ones using Ph3PCCO and simple α-hydroxy esters.

• Development of a mild and selective acylation procedure for pyrrol-2-ones and furan-2-ones using Ph3PCCO.

• Development of a stereoselective synthesis of highly substituted furan-2-ones.

• Construction of complex heterocycles using the Diels Alder methodology.

• Reaction of cyclic ketols with phosphorus ylide Ph3PCCO to generate highly substituted oligocycles.

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4.8 Synthesis of α,β-Carboxylic acids and derivatives 106 4.9. Synthesis of benzyl and p-methoxybenzyl isoureas 109 4.10. Synthesis of oligocyclic and polymer compounds 111 4.10.1. Synthesis of 2-acylcyclopentanols and bicycle derivatives 111 4.10.2. Synthesis of tricyclic Diels-Alder products 112 4.10.3. Synthesis of polymer scavenger PEG-DCT 113 4.10.4. Synthesis of an immobilised ylide 114

5. Summary (Zusammenfassung) 115

6. References 127

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Abbreviations

approx.

arom.

Bn b.p.

cat.

C^q d DBU

DCC

DCM decomp.

DIPEA DMAP DMSO equiv.

Et Et2O EtOAc EtOH gp.

h HMDS Hz i-Bu IMDA

IMWO

i-Pr IR J m m-C Me MeOH MF

approximately aromatic benzyl boiling point catalytic

quartenary carbon atom doublet

1,8-Diazabicyclo[5.4.0]undec- 7-ene

N,N'-

Dicyclohexylcarbodiimide Dichloromethane

decomposition

Diisopropylethylamine 4-Dimethylaminopyridine Dimethylsulfoxide

equivalent Ethyl

Diethyl ether Ethyl acetate Ethanol group hour

Hexamethyldisilazane Hertz

iso-butyl (-CH2CH(CH3)2) Intramolecular Diels-Alder reaction

Intramolecular Wittig olefination

iso-propyl (-CH(CH3)2) infrared

coupling constant multiplet

meta-carbon atom methyl

Methanol

molecular formula

min mL mmol mol m.p.

MS MW n-Bu NMR o-C p-C PCC Pd/C PEG- MME PEG- DCT pet.ether PMB PO Ph PhLi ppm PTSA PTSCl py q r.t.

sec-Bu T TCT Temp.

THF TLC TMS unsat.

↑

minute millilitre millimole mole

melting point Mass spectrometry molecular weight/mass butyl (-(CH2)3CH3)

Nuclear Magnetic Resonance ortho-carbon atom

para-carbon atom

Pyridinium chlorochromate Palladium on charcoal Polyethyleneglycol- monomethyl ether Polyethyleneglycol- dichlorotriazine petroleum ether 4-Methoxybenzene Triphenylphosphine oxide phenyl

Phenyllithium parts per million 4-Toluene sulfonic acid 4-Toluene sulfonyl chloride Pyridine

quartet

room temperature -CH(CH3)CH2CH3

time

Trichlorotriazine temperature Tetrahydrofuran

Thin layer chromatograpy Tetramethylsilane

unsaturated an increase in

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1. General Section

1.1 General Introduction

Naturally occurring compounds isolated from flowers, plants and insects are used for their taste, colour, odour and medical application. Hence, with such a range of applications, it is worthwhile to develop chemical pathways to synthesise these natural products on a large scale.

Natural product chemistry deals with the extraction of naturally occurring compounds, their structure elucidation, function in their natural environment and biosynthesis. A combination of these factors provides a better understanding of the molecule for its total synthesis in the laboratory. The development of general procedures to prepare these naturally occurring compounds not only allows larger scale production, but also facilitates the synthesis of analogues which may not be present in nature.

Analogues of compounds are useful especially in drug development, for comparisons of their structure-activity relationships. A small modification in the structure of a molecule can have a huge impact on its activity. Therefore, by testing analogues of compounds, it is possible to find the most biologically active and potential drug candidate.

The role of the chemist is to search for cost-effective, efficient and versatile syntheses of biologically active compounds, where the overall yield and purity of the final product are not only of immense importance but also the chemical concepts behind each individual step in the synthesis.

Due to the extensive use of keteneylidenetriphenylphosphorane 1a both as a 'CCO' building block in construction of highly functionalised 4-hydroxy-pyrrol-2-ones and 4-hydroxy-furan-2-ones and as an acylating agent, it's structure, properties and characteristic reactions are discussed below.

1.2 Keteneylidenetriphenylphosphorane: Structure and Properties

The electronic structure and distribution of phosphorus 1s² 2s² 2p⁶ 3s² 3p³ allows the formation of tri-, tetra-, penta- and hexa-coordinate derivatives where the ligands can be

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organic or inorganic. The importance and widespread use of organophosphorus compounds stems from the range of possible coordination numbers it can possess, from P^(III) through to P^(VI). The strong bonds phosphorus forms with O, S, N and C, and its capability to stabilise adjacent anions are also important when dealing with reactions of organophosphorus reagents such as ylides (or ylids).

An ylide is defined as 'a substance in which a carbanion is directly attached to a heteroatom carrying a substantial degree of positive charge, and in which the positive charge is created by sigma bonding of the substituents to the heteroatom'^[1]. Phosphacumulene ylides^[2] are described by R3P=C=C=X where R represents a variety of aliphatic and aromatic groups (usually alkyl or phenyl groups) and generally X = O 1a, S 1b or NPh 1c. The resonance structures for phosphacumulene ylides are shown below^[3]:

i ii iii

C C Ph₃P

X Ph₃P C C X Ph₃P C

1a: X = O 1b: X = S 1c:

C X

X = NPh Fig.1

Resonance structures i - iii differ in their geometry and electron distribution depending on the nature of X. As the electron accepting character of X increases, there is less of a tendency of C^β=X to participate in the double bond and so the electronic structure leans towards that of iii. Therefore, from X=NPh 1c to X=O 1a to X=S 1b, the PC^αC^β bond angle increases from approximately 120^o to 180^o and the C^α=C^β bond length shortens^[4]. This has been proven by X-ray structure analysis of compounds 1a^[5], 1b^[6]and1c^[7], as shown in Table 1:

P-C^α bond length (Ǻ) C^α-C^β bond length (Ǻ) PC^αC^β angle (^o)

1a, X = O 1.648 1.210 145.5

1b, X = S 1.677 1.204 168.0

1c, X = NPh 1.677 1.248 134.0

Table 1: Bond lengths and bond angles of phosphacumulene ylides 1a-c.

The differences in the PC^αC^β bond angles can be attributed to the variation in hybridisation of C^α. 1c, which is largely represented by structure i (Fig.1), contains a more sp²-hybridised ylide carbon and a bond angle close to 120^o which produces a triangular shape, while 1b exhibits more sp-hybridisation with structure iii (Fig.1)

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carrying more weight, resulting in a shape close to linear. In general, the C^α=C^β bonds are considerably short in comparison to the normal allene length of 1.31 Ǻ and more in line with the length of alkyne bonds (1.21 Ǻ)^[8], see Table 1. This indicates a substantial contribution from the triple bonded resonance structure iii, especially in 1a and 1b.

The P-Cbond lengths quoted in Table 1 are distinctly shorter than an average single P-C bond (1.85 Ǻ). For many years, this was explained by back-bonding from the ylide carbon (C^α) into the vacant d-orbitals of phosphorus^[9,10], but more recently it is thought that the back-bonding occurs into the phosphorus sp³-hybrid orbitals, with little or no contribution from the d-orbitals.

The stability and reactivity of phosphorus ylides depends largely on the substituents attached to the ylidic carbon atom and somewhat on the phosphorus substituents. Electron donating groups on the phosphorus atom increase the dipole moment of the P-C^α bond, leading to a greater charge separation and a slightly enhanced reactivity. While electron withdrawing groups lower the charge separation, leading to an increase in the participation of resonance structure ii (Fig.1), resulting in a reduction of the ylide reactivity.

In general, electron withdrawing groups e.g. CO2Et and CN attached to the carbon end of the dipole, delocalise the carbanionic charge which reduces the nucleophilicity (i.e. decreasing the ylidic character) of the ylide and hence stabilise it. In contrast, electron donating groups such as alkyl residues, decrease ylide stability by increasing its overall reactivity e.g. Me3P=CH2 2a, Ph3P=CH2 2b and Ph3P=CHMe 2c are customarily prepared in situ due their extreme reactivity.

Keteneylidenetriphenylphosphorane 1a is incorporated into many syntheses as a 'C2O'- building block because of its intermediate stability and reactivity when activated with catalytic quantities of benzoic acid.

Ylides containing alkoxy residues at C^α are rather reactive and even react with sterically hindered ketones, while silyl groups stabilise the negative charge on C^α of an ylide, reducing its reactivity. Ylides with main group metal substituents attached to the ylidic carbon have also been prepared and possess significant nucleophilicity e.g.

lithiated derivatives have the potential to react with even weak electrophiles which are unreactive towards the non-lithiated parent ylide. Finally, ylides with a transition metal substituent at C^αhave also been synthesised but are not commonly used due to their lack of consistency and unproductive reaction procedures.

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Phosphacumulene ylides such as 1a contain four electrons in each orthogonal π-system (Fig.2) i.e. 4 electrons in the 2px orbital system and 4 electrons in the 2py orbital system.

Unlike ketenes with their nucleophilic π⁴- and electrophilic π²-systems, both ylide π⁴- systems are nucleophilic and the lack of electrophilic (and dipolar) character prevents the ylide from dimerising i.e. reacting with a second molecule of itself. Therefore, neutral ylides can only behave as nucleophiles with electrophiles adding across their P-C^α or C^α=C^β bonds.

C

O C

Ph₃P

y

x z

Fig.2 π-system of the zwitterionic structure of ylide 1a.

The π⁴_┴π⁴-electron system of cumulated ylides is transformed into the ketene π⁴_┴π²- system by addition of an electrophile (E⁺) to the ylidic carbon producing phosphonium ion 4 (see Scheme 1^[4]). This activates the ylide for reaction.

If the starting ylide 1a-c is a stronger nucleophile than Nu^- (E-Nu), it will react with 4 via a [2+2]-cycloaddition to form the four-membered ring system 6, of which resonance structures 6i and 6ii are shown (Scheme 1). But if Nu^- is the stronger nucleophile, it will attack C^β of 4 generating compound 5, which can undergo Wittig reactions depending on the nature of E⁺ and Nu^-. The latter reaction is the basis for the use of keteneylidenetriphenylphosphorane 1a throughout this project, allowing the construction of complex organic molecules.

C C Ph₃P

X ^E-Nu C C

Ph₃P

X E

Nu C C

Ph₃P

Nu E X

E = Electrophile Nu = Nucleophile

X Ph₃P

E

X PPh₃ X

Ph₃P E

X

PPh₃ Nu

1a-c

3

4 1a-c

5

6i 6ii

Scheme 1

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1.3 Synthesis of Ph

3

P=C=C=X

Keteneylidenetriphenylphosphorane 1a was first synthesised by Birum and Matthews in 1961^[11] by the electrophilic addition of CO2 8a to hexaphenylcarbodiphosphorane7^[12] in diglyme. The thermolytic conditions used, promoted eviction of the triphenylphosphine oxide furnishing ylide 1a. The thio 1b and imino 1c derivatives were also synthesised^[6,13]by reacting 8b and 8c respectively, with 7.

C PPh₃

Ph₃P ^X ^{C Y}

C C NPh Ph₃P

X=Y=S

X=Y=O X=NR

Y=S

C C S Ph₃P

C C O Ph₃P

7 ⁸

9

8a 8c

8b

1c

1a 1b

-Ph₃P=S -Ph₃P=S

-Ph₃P=O reflux

reflux

PPh₃ Ph₃P

X Y

Scheme 2

Some years later, Bestmann^[14] reacted methylene triphenylphosphorane 2b with dihalo compounds 10 yielding the corresponding phosphacumulene ylides 1b, 1c and 1d:

CH₂

Ph₃P C

Ph₃P

X Hal

Hal ^2b HC C

Ph₃P

X Hal 2b

11 5a

X Hal Hal

C C X

Ph₃P 1b: X = S 1c: X = NPh 1d: X = CR₂

10a: Hal=Cl, X=S 10b: Hal=Cl, X=NPh 10c: Hal=Cl, X=CR₂

- Ph₃PCH₃⁺Hal^-

2b - Ph₃PCH₃⁺Hal^-

Scheme 3

Three equivalents of ylide 2b were needed: to initially react with dihalo compound 10 forming phosphonium salt 11, to dehydrohalogenate 11 to ylide 5a and finally to dehydrohalogenate compound 5a to generate the corresponding cumulated phosphonium ylide 1. This method was highly inefficient due to the large excess of starting ylide 2b needed. An improved synthesis of 1a is described below:

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PPh₃ 13, toluene

Br

O

O Ph₃P

O

O Br

Ph₃P O

O Ph₃P C C O

1a

24 h, r.t.

1M NaOH / H₂O

(HN(SiMe₃)₂ / NaNH₂) toluene, 24 h, 60-70^oC

- NaOMe

12 14

15a Scheme 4

Triphenylphosphane 13 and methyl α-bromo-ethanoate 12 react together to form the air- stable, quartenary phosphonium bromide 14, which precipitates from the reaction mixture. The precipitate is treated with a 1M sodium hydroxide solution causing dehydrohalogenation to ester ylide 15a. The ester ylide is treated with NaN(SiMe3)2

which deprotonates C^α and with the elimination of sodium methoxide, keteneylidenetriphenylphosphorane 1a is produced. NaN(Si(CH3)3)2 can be generated in situ.

When a catalytic amount of hexamethyldisilazane is added to sodium amide in benzene (or toluene) followed by addition of the ester ylide, the reaction conditions needed are milder and the yields notably improve^[15]in comparison to the reaction without (SiMe3)2NH. The use of molar quantities of both HMDS and NaNH2 was even more effective. Simple filtration of the reaction mixture removes the sodium methoxide by-product, followed by evaporation of the volatile hexamethyldisilazane and ammonia by-products leaving ylide 1a in solution. This procedure has also been adapted for the synthesis of the analogous compound 1b^[14a,16].

1.4 Reactions of Keteneylidenetriphenylphosphorane

1.4.1 Dimerisation reactions

The dimerisation of neutral phosphacumulene ylides does not occur due to their π⁴┴π⁴- electron system but when protonated at C^α, the ylide possesses a π⁴┴π²-system enabling it to react immediately with a molecule of 1a:

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O PPh₃

O 16 Ph₃P

C C O Ph₃P ^HCl

1a

HC C Ph₃P

O C C

O PPh₃

4a

1a

O PPh₃

O Ph₃P

Base

Cl

O Ph₃P

H

O PPh₃ O

Ph₃P H

O

PPh₃ Cl

6a

Scheme 5

4a and 1a react via a [2+2]-cycloaddition reaction to generate carbocycle 6a, which forms the stable cyclobutadiene 16 on treatment with base such as NaN(SiMe3)2.

1.4.2 Reactions with Halogen compounds

Phosphacumulene ylides such as 1a readily react with alkyl halides^[17,18] 17 via a nucleophilic substitution reaction to yield highly reactive phosphonium salts 6b:

C C O

Ph₃P ^R-Hal

1a ¹⁷

C C Ph₃P

O R

C C

O PPh₃

4b

1a Hal

O

PPh₃ O

Ph₃P R

Hal

6b

Scheme 6

The π⁴┴π²-electron system of 4b allows an immediate reaction with a molecule of 1a forming cyclic phosphonium salt 6b, which ring-opens on treatment with sodium methoxide^[18].

1.4.3 Reactions with Acidic compounds

1.4.3.1 Synthesis of Carboxylic acid derivatives

Ylide 1a reacts with H-X acidic compounds such as alcohols 18a, thiols 18b and amines 18c forming ion pair 4a, which in turn generates acyl ylides 15, 19 and 20.

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C C O

Ph₃P ^R-XH

1a

C C Ph₃P

O H

4a X R

C C Ph₃P

H

5a X O

R

Ph₃P O

XR

18a: X=O 18b: X=S 18c: X=NR

15: X = O 19: X = S 20:X = NR Scheme 7

The activated, protonated ylide does not react with a second equivalent of 1a because of the higher nucleophilicity of RX^-.

Ylides 1a and 1c (Ph3PCCNPh) react readily with alcohols, thiols and acidic N-H compounds, however 1b (Ph3PCCS) reacts with thiols and phenols, less rapidly with aliphatic alcohols and not at all with N-H acids^[4].

Ester ylides 15 react with aldehydes 21 via a Wittig-olefination reaction yielding α,β- unsaturated esters 24^[4].

Ph₃P O 15 OR

Ph₃P O

OR O R'

H

21

Ph₃P

O OR

O

H R' O

OR R'

22a 23a

24

O R' H

- Ph₃PO

Scheme 8

This is a valuable reaction because ester ylides 15 can be subjected to reactions while the alkene function is masked as an ylide and at the end of the synthesis, the phosphorus group is expelled furnishing a new P-free compound.

If the ester ylide and carbonyl functionalities are part of the same molecule, they react via an intramolecular Wittig-olefination resulting in ring closure, and with eviction of triphenylphosphine oxide, a cyclic compound containing a double bond is generated:

Ph₃P O

X

O R

Ph₃P O

X O R

O X R

Scheme 9

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The addition of amines and alcohols to keteneylidenetriphenylphosphorane 1a, followed by an intramolecular Wittig reaction (Scheme 9) is a particularly useful sequence of reactions in this project as it generates 5-membered oxygen and nitrogen containing heterocycles.

This type of reaction is rather flexible in terms of linkage possibilities between the ylide and carbonyl functionalities, as well as the nature of other functional groups present in the molecule which do not take part in the Wittig reaction. This opens doors for interesting and versatile syntheses of heterocycles of various sizes and containing different heteroatoms.

1.4.3.2 Addition of C-H acids

Keteneylidenetriphenylphosphorane 1a reacts with compounds of type CH2RR', where R and R' are electron-withdrawing groups e.g. 1,3-dicarbonyl compounds 25, generating products such as 26.

O R

O R'

O R

O

C C O R'

Ph₃P

1a ²⁵

Ph₃P O

O R

O R' Ph₃P O

26 Scheme 10

Due to extensive delocalisation of electrons across 'the former ylide portion' of 26, it exists as the tautomeric forms shown above and cannot undergo further Wittig reactions^[4].

1.4.4 Reaction with Aldehydes and Ketones

Generally, 1a undergoes addition reactions across its C^α=C^β bond. The only exception is found in its reaction with aldehydes 21 or ketones 27, where the carbonyl group of the aldehyde/ketone adds across the ylidic P-C^α bond of 1a, as shown in Scheme 11^[19]. 27 adds to 1a in a [2+2]-cycloaddition reaction, forming the unstable, four-membered cyclic intermediate 28, which reacts in either of two ways; with a second equivalent of 1a followed by elimination of Ph3PO to form 30 or by breaking down, evicting triphenylphosphine oxide and the ketene product reacts with ylide 1a generating the four-membered carbocycle 30.

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C C O Ph₃P

1a Ph₃

P

O C O

R R' 28

Ph₃ P O R R'

29 O

PPh₃ O

C O

PPh₃ O

R R' C C O

C R

R' 31

30 O

R R' 21: R=H, R'=alkyl 27: R=R'=alkyl

1a

-Ph₃PO -Ph₃PO

Scheme 11

1.4.5 Cycloaddition reactions to other double bonds

1.4.5.1 Reactions with Ketenes

Ketenes 32 add across the C^α=C^β of keteneylidenetriphenylphosphorane 1a in a [2+2]- cycloaddition fashion to produce 1,3-cyclobutadienones 33^[4]:

C C O Ph₃P

C

O C

R 32 R'

1a Ph₃P O

R² O

R¹ 33 Scheme 12

1.4.5.2 Reactions with isocyanates and isothiocyanates

Addition of carbon disulfide 8b across the C^α=C^β bond of 1a forms the four-membered heterocycle 34, which decomposes via a cycloreversion to give thioketeneylidenetriphenylphosphorane 1b and COS 8d^[20]:

C C O Ph₃P

C

S S

8b 1a

S Ph₃P O

S 34

S Ph₃P O

S

C C S

C Ph₃P O

S

1b 8d Scheme 13

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But isocyanate 8e and ylide 1a react in a 2:1 molar ratio to generate the neutral, 6- membered heterocyclic phosphorane, barbituric acid derivative 36^[20,21]. Isothiocyanates 8c also react with keteneylidenetriphenylphosphorane 1a in a 2:1 molar ratio, but because of the higher nucleophilicity of the sulphur atom (over the nitrogen), the 6- membered dithiane 37 is formed.

C C O Ph₃P

1a

Ph₃P O

S NR 35b

S S

NR RN

O Ph₃P

37

RN=C=O

RN=C=S RN=C=S

8e

8c 8c

Ph₃P O

O NR

35a 36

NR NR O Ph₃P

O O

RN=C=O 8e

Scheme 14

1.4.6 Multi-component reactions

The multi-component reaction is a method of conveniently preparing the backbone of complex organic structures that may be otherwise difficult using conventional multistep syntheses. The three component, 'one-pot' reaction of a cumulated ylide 1a, an alcohol 18a and an aldehyde 21 generates α,β-unsaturated esters 24:

C C O Ph₃P

1a

R'CHO

THF / Toluene, reflux, 12 - 24 h.

-Ph₃PO

O OR R' 24

18a 21

+ ROH + Scheme 15

Ylide 1a deprotonates the alcohol, leaving RO^- to react with the carbonyl group of the ketenylidium cation producing an ester ylide intermediate (compound 15, Scheme 7).

The aldehyde 21 reacts with this ester ylide via a Wittig olefination reaction* to give the α,β-unsaturated ester 24. This reaction also works well for the synthesis of the corresponding thioesters and amides^[22].

*The mechanism of which is discussed in Section 1.5.

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1.5 The Wittig Reaction

1.5.1 General

The Wittig reaction, although first discovered in the 1920's by Staudinger and students^[23,24], was developed and made known by Georg Wittigand co-workers^[25] in the early 1950's. Wittig reacted aldehydes 21 and ketones 27 with phosphorus ylides 2 producing alkenes 38, with no ambiguity about the position of the double bond:

R₃P CHR' R"CHO

O R"

H

H R'

PR₃ PR₃

O R"

H

H R'

R"

R' H

H 2 21

22 23

38ii

- R₃P=O

+

H R' R''

H 38i Scheme 16

The Wittig reaction has become a cornerstone in organic synthesis because it is:

9 regiospecific with respect to the double bond 9 effective using relatively mild reaction conditions

9 often carried out in the presence of other functional groups

9 efficient as a 'one-pot' reaction where the phosphorus group is also removed as the corresponding oxide

9 often stereoselective depending on the nature of the ylide, the carbonyl components and the experimental conditions used.

The discovery of the Wittig reaction^[25] prompted the widespread use of triphenylphosphonium ylides (over other ylides) due to the easy accessibility of Ph3P and the chemoselectivity of deprotonation in the final step of ylide synthesis.

The nature of the carbanion substituents of the ylide has a major influence on the Wittig activity of the ylide. Those ylides with strong carbanion-stabilising groups, e.g.

triphenylphosphine cyclopentadieneylide, are of insufficient nucleophilicity to react with aldehydes or ketones^[26], while ylides with electron-donating groups such as alkyl or vinyl residues readily react with aldehydes, but more sluggishly with ketones^[27,28].

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The nature of the carbonyl reactant also affects the feasibility of the Wittig reaction.

Clearly the reactivity of the carbonyl group is determined by its electrophilicity, with aldehydes more prone to attack by nucleophiles than ketones. Therefore, almost any variation of aldehyde, even sterically hindered ones, can participate in the Wittig reaction but only certain ketones can be used.

1.5.2. Mechanism of the Wittig Reaction

The Wittig reaction occurs by nucleophilic attack of an ylide carbanion 2 at the carbonyl carbon of an aldehyde 21 (or ketone) to form what was assumed to be 'betaine' 22. This intermediate cyclises to the unstable oxaphosphetane system (or OPT) 23 and subsequently breaks down to the corresponding olefin 38 and phosphane oxide (see Scheme 16). However, there has been much debate whether the betaine or oxaphosphetane intermediates actually exist and if so, how they influence the stereochemical course of the reaction.

In the 1960's, just after the discovery of the Wittig reaction, it was believed that both betaines^[25,29] and OPT's^[25a] were likely intermediates. Although some 10 years later, more emphasis was placed on the dipolar betaine intermediate due to experimental data attempting to prove its existence^[25,30]. Oxaphosphetanes (OPT's) were not considered 'true' intermediates but simply transition states from the betaine 'en route' to the final products. But in the late 70's, betaines were abandoned as likely intermediates because they could not be isolated but only trapped as salts^[25,30] and the emphasis was redirected towards OPT's, which were isolatable. The 'betaine' proposal could not justify the stereoselectivity of various Wittig reactions.

Therefore, the general mechanism in Scheme 16 is not an up-to-date description of the Wittig mechanism, but modern chemists rely more on a proposal put forward by Vedejs^[31]. This consists of a four-centred transition state, the geometry of which is believed to govern the geometry of the subsequently formed OPT, in turn determining the stereochemistry of the Wittig products.

Non-stabilised, reactive ylides form 'early' transition states with non-planar or 'puckered' geometries and a close to tetrahedral phosphorus, see 39i. The aldehyde molecule takes up a pseudo-equitorial orientation in relation to the ylide and the alkyl group attached to the ylidic carbon assumes a pseudoaxial position. As a result of this geometry, there is maximum separation between the aldehyde and ylide (both the

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phosphorus and C^α) substituents. 1,3-interactions dominate in this structure favouring a cis-selective reaction; the intermediate is more stable as the cis-oxaphosphetane 39i and the Z-alkene product is favoured. Formation of an intermediate with planar geometry 39ii is not favoured due to severe methyl-alkyl interactions. The Z-selectivity of this reaction is reduced by using unbranched aldehydes.

P Ph¹ Ph²

O

CH₃

CH₃ CH₃

H Ph³

R

P O

Ph¹ Ph³

H₃C CH₃ CH₃ R

H H Ph²

39i 39ii

H

Fig.3 39i: non-planar geometry of cis-arranged 'early' transition state 39ii: unfavourable planar cis geometry.

On the contrary, stabilised ylides form late, product-like, planar transition states with an almost trigonal bipyramidal phosphorus atom (39iii):

P H

O Ph¹

Ph³ R

H₃C CH₃ CH₃ H Ph²

P Ph¹ Ph²

O

CH₃ CH₃ Ph³

R

H₃C HH

39iii 39iv

Fig.4 39iii: planar geometry of E-arranged 'late' transition state, 39iv: unfavourable non-planar trans geometry.

Here, 1,2-interactions dominate, promoting a trans-selective reaction and favouring formation of the E-alkene. 1,3-interactions which destabilise 39iii depend on the aldehyde substituents e.g. an aldehyde bearing an α-hydrogen could orientate itself so the hydrogen points towards the PPh3 group, reducing these 1,3-interactions and stabilising the structure. The alternative trans-selective geometry 39iv is not favoured due to steric repulsion between Ph¹ and an α-methyl group of the aldehyde.

In conclusion, the 1,2- and 1,3-interactions which greatly influence the cis/trans- selectivity of the Wittig reaction can be enhanced or reduced by careful choice of both the ylide and aldehyde substituents^{[30, 32]}.

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Factors affecting the stereochemistry of the Wittig reaction

In general, stabilised ylides^[33] such as ester ylides promote a E-selective Wittig reaction, semi-stabilised ylides show no preference, while non-stable, reactive ylides^[34] e.g. alkyl ylides, favour production of the thermodynamically less stable Z-olefins. However, there are exceptions to this rule.

The ylide phosphorus substituents affect the reactivity of the ylide and have little or no influence on the stereochemical outcome of the Wittig reaction. However, replacement of one or more phenyl ligands of a triphenylphosphonium ylide with a 2- methoxy-phenyl group enhances the stereoselectivity of the reaction^[35]. Trialkyl phosphorus ylides have also been known to promote high E-stereoselectivity^[36].

The carbonyl compound used in the Wittig reaction greatly affects the rate of the reaction and can also improve the stereoselectivity of the reaction^[37] e.g. non-stabilised ylides react with bulky, aliphatic aldehydes such as (CH3)3CCHO, exhibiting improved Z-alkene stereoselectivity in comparison to less bulky, unbranched aldehydes.

Lithium salts are known to exert a profound effect on the stereochemistry of the Wittig reactione.g. reactive ylides promote E-selectivity in the presence of lithium salts in comparison to the 'normal' Z-selectivity^[38]. Dilution of the reaction mixture, use of solvents which solvate the lithium cation or other complexation possibilities for the lithium cation e.g. addition of alcohols or crown ethers^[39], can significantly reduce this effect.

Wittig reactions of unstable ylides, without organolithium bases, produce high ratios of Z:E-isomer products e.g. the reaction of triphenyl-propylylide and hexanal produced a Z:E olefin ratio of 96:4 in the presence of NaN(SiMe3)3 and only a 50:50 ratio when n-BuLi was used^[40]. Therefore, the preparation of ylides using 'salt-free' methods i.e. the use of a base which is not an organolithium one, are highly beneficial and have attracted much interest.

The choice of solvent used in Wittig reactions can also affect the stereoselectivity of the reaction. The reaction of unstable ylides in aprotic solvents such as THF, are Z- selective^[30,41], while use of polar aprotic solvents such as DMF, give a 50:50 mixture of the olefinic products^[39,42].

In summation, the stereoselectivity of the Wittig reaction may be optimised by careful choice of the ylide, carbonyl compound and reaction conditions.

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1.5.3 'Non-classical' Wittig Reactions

The reaction between a phosphorane 2 and a carboxylate derivative 40 such as a carboxylic ester, an amide etc, generates a heterosubstituted alkene 41 and is known as a 'non-classical' Wittig reaction^[43]:

R¹ PR₃

R² R³ O

XR⁴

R³ XR⁴ R¹ R²

2 40

41

-R₃P=O

+

Scheme 17

1.5.3.1 Wittig Reactions with carboxylic esters

Carboxylic esters and phosphoranes undergo intermolecular or intramolecular Wittig reactions generating acyclic, carbocyclic or heterocyclic products e.g. the reaction of 2d with a simple ester 40a yields β-ketophosphorane 42a^[43a,44]:

PPh₃ Pr

2d

Bu O

OEt Bu PPh₃

- EtOH

O

Pr

+

40a 42a Scheme 18

But when the propyl residue of 2d is substituted with a strong electron-withdrawing group, Wittig products i.e. the phosphorus-free alkene and phosphine oxide are produced. However, this concept is not clear-cut. It has been shown that variation of the temperature or the presence of alkali salts can produce a mixture of both the β- ketophosphorane and olefin products^[44].

Reaction of keteneylidenetriphenylphosphorane 1a and α-hydroxy ester 43 generates ester ylide 44, which undergoes an intramolecular Wittig cyclisation to the corresponding tetronate 46^[45] and phosphane oxide:

R'

O O 43

R OH

1a

O O

O R'

RO PPh₃

O PPh₃ O

R' O RO

O O

R' RO 44

45

46

- Ph₃P=O

5 3 2

Scheme 19

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The reaction described above is generally not stereoselective, although there are some exceptions^[45]. This reaction has also been applied to the synthesis of thiotetronatesand tetramates^[46], benzofurans and chromenes^[47], dihydrofurans^[48] and bicyclic heterocycles^[49].

When R = allyl, a Claisen rearrangement to C-3 of 46 takes place yielding the α,γ- disubstituted tetronic acid^[45]. This reaction is temperature dependent.

1.5.3.2 Wittig Reactions with amides

Amides are much less susceptible to nucleophilic attack than esters and only the more reactive ylides can alkenate them, typically in an intramolecular process. Pyrroles 48 were synthesised by an intramolecular Wittig condensation of 47^[43]:

N O PPh₃

Ar NC

R

Ph Ar N Ph

R

heat, DMF, 20 - 24 h.

47 48

- HCN - Ph₃P=O

Scheme 20

The cyanide residue adjacent to the amide functionality of 47 influences the conjugation of the nitrogen lone pair across the amide, thus increasing amide reactivity for reaction with the ylide residue. There are no reports of intramolecular Wittig reactions with simple, less substituted amides.

1.5.3.3 Wittig Reactions with thiol esters

The 'non-classical' intermolecular Wittig reaction of thiol esters is of limited use as β- ketophosphoranes are generally formed over the olefinic products^[50]. But the intramolecular reaction has attracted some interest, especially in the synthesis of penem and carbapenem antibiotics^[51] e.g.:

N

R S

O PPh₃

Bu^tO₂C O

N R S

O CO₂^tBu

heat, toluene

49 50

- Ph₃P=O

Scheme 21

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2. Original work: Tetramic Acids

2.1 Introduction

Tetramic acids possess a common pyrrolidine-2,4-dione nucleus (Fig.5) with the possibility of diversity at C-3 and C-5 of the heterocycle. A number of biologically active tetramic acids possess a 3-acyl substituent which contributes to their antibiotic, antiviral and antifungal activity^[52,53].

NH O O

NH O HO

R' R R'

R

2 3 5

51α 51β

Fig.5

The pyrrolidine-2,4-dione system 51 is a useful intermediate in a total synthesis because of the variety of reactions it can undergo^[54]:

• Reactions with electrophiles at C-3 e.g. acyl halides, bromine

• Reactions of organometallic bases such as BuLi at 3-H

• Acylation of 4-OH and possibly 1-H

• Nucleophilic attack at C-4

1-H tetramic acids are generally represented by the keto tautomer pyrrolidine-2,4-dione 51β, with the corresponding enol variant 51α present only as the minor isomer^[55]. Tetronic acids (4-hydroxy-furan-2-ones) exist mainly as the enol tautomer. When tetronic acid (4-hydroxy-furan-2(5H)-one) was first prepared in 1896^[56], experimental data proved the major tautomer to be the 3,4-enol form and so it was automatically expected that tetramic acid, due to its similarity in structure, would also exist mainly as the 3,4-enol tautomer. But contrary to this proposal, in 1972 the first synthesis of 51a (R=R'=H)^[55] revealed it to be a much weaker acid than its oxygen analogue and not highly enolised. Experimental data has since backed up this theory and as a result, tetramic acid 51a is now generally accepted as existing predominantly in the 2,4-diketo form β.

In the mid 1950's, Lacey^[57] synthesised α-acetyl-tetramic acids 54 from N- acetoacetyl amino esters 53 via an intramolecular Claisen condensation reaction

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(Scheme 22). This method was also applied to the synthesis of 3-polyenoyl tetramic acids^[58].

NH O

O

O OR' NH₂ R

O OR'

R N

H O O HO

R 52a: R=H, R'=Et 53a: R=H, R'=Et

diketene NaOMe

54a: R=H Scheme 22

The use of various amino acids as starting materials introduces flexibility at the 5- position of the pyrrolidine ring, but the basic conditions used for ring closure limits the applicability of the reaction with unstable molecules and may induce racemisation at C-5 of an optically pure starting compound. Other syntheses of 3-substituted tetramic acids include:

• Reaction of active methylene compounds 56 with N-hydroxysuccinimide esters of N-Boc amino acids 55, followed by an intramolecular condensation to the corresponding N-alkoxy 3-substituted tetramic acid 58^[59]:

NH O O H

N O

O Boc

H₂C R'

CO₂R NHCO₂R Boc H

HO R'

N H

HO R'

O Boc +

58 56

57 55

Scheme 23

• Dieckmann cyclisation of N-acyl α-amino esters followed by hydrolysis and subsequent acylation^[60].

• Solid-phase synthesis from a resin-bound α-amino acid, which is functionalised to the corresponding amide, followed by a base-induced cyclisation^[61].

One of the more simplistic tetramic acids is Tenuazonic acid, the structure of which was elucidated by Stickings^[53] in 1959 as 3-acetyl-5-sec-butyl-4-hydroxy-∆³-pyrrolin-2-one 54b:

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NH O 54b

O

H HO H

Tenuazonic acid was first isolated in 1957 from culture filtrates of the Alternaria tenuis organism by Rosett et al^[62] and a couple of years later, Stickings^[53] showed that it was biosynthetically derived from L-isoleucine and identified the absolute configuration of the chiral centres to be 5S,6S. Interestingly, the biosynthetic pathway was found to proceed by reaction of 2 equivalents of acetate with L-isoleucine via N-acetoacetyl-L- isoleucine, rather than ring closure followed by 3-acylation by the second acetate molecule.

Tenuazonic acid 54b is known to possess a low level of antibacterial activity^[63]

and has an inhibitory effect on many viruses^[64]. It has been shown to inhibit adenocarcinoma growing in the human embryo by inhibiting the incorporation of amino acids into the microsomal protein^[65]. The activity of 54b is believed to result from a combination of the pyrrolidine-2,4-dione ring, the chirality at C-5, the 3-acyl functionality and its ability to form complexes with metal ions^[66]. Although, tenuazonic acid 54b has the potential to be useful in medicine, its toxicity has impeded its clinical application to date.

The aim of the project was to synthesise tenuazonic acid 54b by using keteneylidenetriphenylphosphorane 1a in construction of the pyrrolidine-2,4-dione framework. The synthesis should be sufficiently flexible in order to prepare a number of derivatives.

A more complex member of the family of tetramic acids is the N-functionalised Reutericyclin 59 which is thought to possess a wide range of biological activity including antiulcerative properties, inhibition of tumours and fungicidal activity^[67]. But because of its particularly recent isolation and characterisation, the true medicinal potential of reutericyclin 59 has not yet been realised.

Keteneylidenetriphenylphosphorane as a 'C2O building block' in the synthesis of highly functionalised tetramic and tetronic acids